State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China; Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Cancer Research Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen 518055, China.
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
Cell Rep. 2024 Sep 24;43(9):114662. doi: 10.1016/j.celrep.2024.114662. Epub 2024 Aug 22.
Ferroptosis is a form of nonapoptotic cell death characterized by iron-dependent peroxidation of polyunsaturated phospholipids. However, much remains unknown about the regulators of ferroptosis. Here, using CRISPR-Cas9-mediated genetic screening, we identify protein arginine methyltransferase 1 (PRMT1) as a crucial promoter of ferroptosis. We find that PRMT1 decreases the expression of solute carrier family 7 member 11 (SLC7A11) to limit the abundance of intracellular glutathione (GSH). Moreover, we show that PRMT1 interacts with ferroptosis suppressor protein 1 (FSP1), a GSH-independent ferroptosis suppressor, to inhibit the membrane localization and enzymatic activity of FSP1 through arginine dimethylation at R316, thus reducing CoQ10H2 content and inducing ferroptosis sensitivity. Importantly, genetic depletion or pharmacological inhibition of PRMT1 in mice prevents ferroptotic events in the liver and improves the overall survival under concanavalin A (ConA) exposure. Hence, our findings suggest that PRMT1 is a key regulator of ferroptosis and a potential target for antiferroptosis therapeutics.
铁死亡是一种非细胞凋亡的程序性细胞死亡形式，其特征是依赖铁的多不饱和磷脂过氧化。然而，关于铁死亡的调节因子，仍有许多未知之处。在这里，我们使用 CRISPR-Cas9 介导的遗传筛选，鉴定出蛋白精氨酸甲基转移酶 1（PRMT1）是铁死亡的关键促进因子。我们发现 PRMT1 降低溶质载体家族 7 成员 11（SLC7A11）的表达，从而限制细胞内谷胱甘肽（GSH）的丰度。此外，我们表明 PRMT1 与铁死亡抑制蛋白 1（FSP1）相互作用，FSP1 是一种不依赖 GSH 的铁死亡抑制蛋白，通过 R316 上的精氨酸二甲基化来抑制 FSP1 的膜定位和酶活性，从而降低 CoQ10H2 的含量并诱导铁死亡敏感性。重要的是，在小鼠中遗传耗尽或药理学抑制 PRMT1 可防止肝脏中的铁死亡事件，并在伴刀豆球蛋白 A（ConA）暴露下提高整体存活率。因此，我们的研究结果表明 PRMT1 是铁死亡的关键调节因子，也是抗铁死亡治疗的潜在靶点。
